CH. 369: POLIOMYOSITIS (PM), DERMATOMYOSITIS (DM) & INCLUSION BODY MYOSITIS (IBM)

The inflammatory myopathies, classified into 3 groups: a.) DM, b.) PM, c.) IBM, represent the largest group of acquired and potentially treatable causes of skeletal muscle weakness.

Clinical Features

DM: children> adults, F> M IBM: M> F, Caucasian> Blacks, persons >50 y/o These disorders present as progressive, symmetric

muscle weakness Increasing difficulty with tasks requiring use of proximal

muscles (i.e.climbing steps, combing hair) Fine-motor movements that depend on strength of

distal muscles: late in PM and DM; early in IBM Falling is common in IBM due to early involvement of

quadriceps muscles with buckling of knees Ocular muscles are spared Facial muscles: unaffected in PM and DM; mild

weakness in IBM All forms: pharyngeal and neck flexor muscles are

involved causing dysphagia or difficulty in holding head up (head drop)

Respiratory muscles involved in advanced and rarely acute cases

Severe weakness if untreated associated with muscles wasting

Sensation: normal Tendon reflexes are preserved but may be absent in

severely weakened or atrophied muscles especially in IBM, where atrophy of distal muscles and quads are common

Myalgia and muscle tenderness may occur early in disease particularly in DM associated with CT disorders

Weakness progression: subacutely over weeks/months, rarely acutely in PM and DM; very slowly (years) stimulating a late-life muscular dystrophy or progressive motor neuron disorder in IBM

Specific FeaturesA. Polymyositis

Actual onset not easily determined Patients delay seeking medical advice Mimics many other myopathies and is diagnosis of

exclusion Subacute inflammatory myopathy affecting adults,

rarely children, who do not have any of the ff:o Rasho Involvement of extrocular and facial

muscleso Family hx of neuromuscular diseaseo History of exposure to myotoxic drugs or

toxinso Endocrinopathyo Neurogenic diseaseo Muscular dystrophyo Biochemical muscle disorder (muscle

enzyme deficiency)o IBM as excluded by muscle biopsy

analysis Occurs in association with systemic, autoimmune ,

or connective tissue disease, or with known viral or bacterial infection

Drugs (i.e. D-penicillamine, zidovudine (AZT)) may produce inflammatory myopathy similar to PM

B. Dermatomyositis Identified by characteristic rash, accompanying or

preceding muscle weakness Rash, which worsens after sun exposure, may

present as: o Heliotrope Rash: blue-purple

discoloration on upper eyelids with edema

o Gottron Rash: erythema on knuckles with raised violaceous scaly eruptions

o V sign: erythematous rash on neck and anterior chest

o Shawl Sign: rash on back and shoulderso Flat red rash on face and upper trunk,

knees, elbows, malleoli Rash may be pruritic, especially on scalp, chest,

and back Dilated capillary loops at the base of the

fingernails Mechanic’s hands: irregular, thickened and

distorted cuticles; lateral and palmar areas of finger are rough and cracked, with irregular “dirt” horizontal lines

Muscle strength may appear normal, hence, the term: dermatomyositis sine myositis

Usually occurs alone but may overlap with scleroderma and mixed CT disease

Fasciitis and thickening of the skin similar to that seen in chronic cases have occurred in patients with eosinophilia-myalgia syndrome associated with ingestion of contaminated L-tryptophan

C. Inclusion Body Myositis Most common of the inflammatory myopathies

among 50 years old and above Often misdiagnosed as PM and only suspected

later when presumed PM does not respond to therapy

Weakness and atrophy of distal muscles, especially foot extensors and deep finger flexors (clue to early diagnosis)

Knees collapse due to early quadriceps weakness Weakness in small muscles of the hands leading

to inability to hold objects Occasionally, weakness and atrophy may be

asymmetric and selectively involve the quads, iliopsoas, triceps, biceps and finger flexors, resembling LMN disease

Dysphagia may occur leading to choking Sensory exam: normal Mildly diminished vibratory sensation at the angles

presumable age-related Pattern of distal weakness (resemble motor

neuron or peripheral nerve disease) results from myopathic process affecting distal muscles

Disease progression is slow Most require assistive devices such as cane,

walker Familial Inflammatory IBM: familial aggregation of

typical IBM Hereditary IBM (h-IBM): heterogenous group of

recessive, less frequently dominant inherited syndrome; non-inflammatory myopathies

Subset of h-IBM: spares quadriceps linked to chromosome 9p1 and results from mutations in the GNE gene

Associated Clinical FindingsA. Extramuscular Manifestations

- may present to varying degree in PM or DM, including:

1. Systemic symptoms: fever, malaise, Raynaud’s phenomenon especially when associated with CT disorder

2. Joint contracture, mostly in DM and especially children

3. Dysphagia and GI symptoms due to involvement of oropharyngeal striated muscles and upper esophagus especially in DM and IBM

4. Cardiac disturbances: including AV conduction defects, tachyarrythmas, dilated cardiomyopathy, and low ejection fraction. CHF and myocarditis from diseases itself or from HPN due to use of glucocorticoids

5. Pulmonary dysfunction: due to weakness of thoracic muscles, interstial lung disease, or drug –induced

pneumonitis that can cause dyspnea, aspiration pneumonia, nonprod. Cough

6. Subcutaneous calcifications: in DM, extruding on skin and causing ulcerations and infections

B. Association with Malignancies Increased only in patients with DM, not in PM or

IBM Most common tumors associated with DM: ovarian

CA, breast CA, melanoma, colon CA and non-Hodgkin lymphoma

Tumors are usually uncovered by abnormal findings in the history and P.E.

Common annual P.E. (urinalysis, CBC, CXR, pelvic, breast exam) would suffice

Nasopharyngeal CA: common in Asians

C. Overlap Syndromes Association with CT diseases DM can have manifestations of systemic sclerosis

or mixed CT disease (i.e. calcium deposits, contractures)

Signs of R.A., SLE, or Sjoregren’s syndrome rare in DM

DM + systemic sclerosis: have specific ANA, the anti-PM/Scl

Pathogenesis-an autoimmune etiology is indirectly supported by

association with other CT diseases; presence of autoantibodies, association with MHC; demonstration of T cell-mediated myotoxicity or complement-mediated microangiopathy; & response to immunotherapy.

A. Autoantibodies and Immunogenetics Antibodies to cytoplasmig antigens are directed

against riboucleoprotiens involved in protein synthesis (anti-synthetase) or translational transport (anti-signal-recogntion particles)

Anti-Jo-1: Ab directed against histidyl-transfer RNA synthetase with majority of patients having interstitial lung disease; accounts for 75% of all anti-synthetases

May also have Raynaud’s phenomenon, nonerosive arthritis and MHC molecules DR3 and DRw52

B. Immunopathologic Mechanisms DM

o Humoral immune mechanisms, resulting in microangiopathy and muscle ischemia

o Endomysial inflammatory infiltrates composed of B cells located in proximity to CD4 T cells and macrophages

o Relative absence of lymhocytic invasion of nonnecrotic muscle fibers

o Complement C5b-9 membranolytic attack complex activation triggers release of cytokines and chemokines, induce expression of VCAM 1 and ICAM1 on endothelial cells, and facilitates migration of activated lymphoid cells to the perimysial and endomysial spaces

o Occurrence of endothelial cell necrosis, decreased endomysial capillaries, ischemia and muscle-fiber destruction

o Remaining capillaries have dilated lumens due to ischemia

o Residual perifascicular atrophy reflects endofascicular hypoperfusion that is prominent in periphery of muscle fascicles

PM and IBMo T cell mediated cytotoxicity o CD8 t cells with macrophages invade and

destroy healthy muscle fibers that express class I MHC

o Cytokines secreted induces MHC-I expression

o CD8/MHC-I complex characteristic of PM and IBM

o Cytotoxic CD8 T cells contain perforin and granzyme granules directed towards muscle fibers inducing myonecrosis

C. Role of Non-immune Factors in IBM Presence of vacuoles with B-amyloid deposits

within vacuolated muscle fibers and abnormal mitochondria with cytochrome oxidase-negative fibers suggest autoimmune component and degenerative process

Amyloid deposits are immunoreactive against amyloid precursor protein (APP), chymotrypsin, apolipoprotein E, and phosphorylated tau.

Mitochodrial abnormalities secondary to aging or bystander effect of upregulated cytokines

D. Association with Viral Infections and Role of Retroviruses

Coxsackieviruses: autoimmune myositis triggered by molecular mimicry due to structural homology between histidyl-transfer RNA synthetase that is target of Jo-1 antibody and genomic RNA of encephalomyocarditis virus

Retroviruses: best evidence of viral connection in PM and IBM; distinguished from toxic myopathy related to long-term therapy with AZT (inhibits y-DNA polymerase, an enzyme found in mitochondrial matrix)

o AZT-induced myopathy: mitochondrial disorder characterized by “ragged red” fibers

Differential Dx Skin rash w/ proximal or diffuse muscle weakness has

few causes other than DM Proximal weakness w/ out rash has many causes other

than PM or IBM

A. Subacute or Chronic Progressive Muscle Weakness Denervating muscle conditions

- Spinal musclular atrophies- Amytrophic Lateral Sclerosis- Weakness followed by UMN signs

and denervation on EMG Muscular Dystrophy

- Rare over 30 y/o- Develop over years no months

Difficult to differentiate chronic PM vs rapidly advancing muscular dystrophy even with biopsy

- Ex- facioscapulohumeral muscular dystrophy, dsyferlin myopathy, and dystrophinopathies all with early inflammatory cell infiltrate

- Dx- glucocorticoid trial tx and detection of MHC/CD8 by immunohistochem

Metabolic myopathies dx via muscle biopsy:- glycogen storage disease due to

myophosphorylase or acid maltase deficiency

- lipid storage myopathy due to carnitine deficiency

- mitochondrial diseases Endocrine myopathy

- hypercorticosteroidism- hyper/ hypothyroidism- hyper/ hypoparathyroidism

Muscle wasting w/ neoplasm due to cachexia, disuse, rare to paraneoplastic myopathy

NMJ diseases- myasthenia gravis- Lambert Eaton Myasthenic

syndrome- both with fatiguing weakness, eye

and cranial nerve weakness- dx- repetitive nerve stimulation and

EMG

B. Acute Muscle Weakness Guillain Barre Syndrome, transverse myelitis,

a neurotoxin, or viral infection such as polio or West nile virus

Acute weakness + painful muscle cramps, rhabdomylosis, myoglobinuria- Metabolic disorders including glycogen

storage disease such as myophosphorylase deficiency or carnitine palmityltransferase deficiency

Acute viral infection Parasites, Parasitic polymyositis

- protozoa (toxoplasma, trypanosome)- cestodes (cysticerci)- nematodes (trichinae)- with focal or diffuse inflammatory

myopathy Anaerobic suppuroative myositis aka Tropical

polymyositis- Staph Aureus, Yersinia, and Strep

Begins in childhood= periodic paralysis developing into recurrent painless acute muscle weakness

Chronic Alcoholics present as:1. Painlful myopathy with myoglobinuria2. Painless, acute hypokalemic, reversible

myopathy3. Asymptomatic Inc serum CK and

myoglobin- Diff Dx of acute muscle weakness w/

myoglobinuria is severe hypokalemia or hypophosphatemia (+) hypomagnesia

- Also common in px w/ parenteral hyperalimentation

C. Macrophagic Myofasciitis Inflammation w/ diffuse myalgia, fatigue, mild

muscle weakness Biopsy shows connective tissue infiltration with

CD8 and PAS positive macrophages Limited to France and to previous sites of vaccine

w/ aluminum containing substrate

D. Drug Induced Myopathies Resembles true PM from D-Penicillamine and

procainamide DM-like with L-tryptophan AZT causes mitochondrial myopathy Toxic noninflammatory myopathy is histologically

different from PM, DM, or IBM:- Cholesterol lowering clofibrate,

lovastatin, simvastatin, provastatin esp when combined w/ cyclosporine or gemfibrozil may elicit this reaction

Rhabdomylosis and myoglobinuria- associated with Amphotericin B,

aminocaproic acid, fenfluramine, heroin Myopathic muscle weakness

- use of amiodarone, chloroquine, colchicines, carbimazole, emetine, etretinate, ipecac syrup, chronic laxative or licorice use causing hypokalemia, and glucocorticoid or growth hormone administration

Pancuronium w/ glucocorticoid cause acute critical illness myopathy

Careful drug Hx is necessary Immunosuppressive Tx is NOT necessary

E. Pain on Movement and Muscle Tenderness Polymyalgia rheumatica and arthritic disorders of

adjacent joints cause inflammatory myopathy without myositis

Normal Biopsy or Type II muscle fiber atrophy FIbrositis and Fibromyalgia present as:

1. Focal/ diffuse muscle tenderness, fatigue, aching

2. Signs of collagen vascular disorder like increased ESR, antinuclear antibody, or rheumatoid factor

3. Slight but transient increase in serum CK- Muscle biopsy Normal and prognosis

good- Respond to NSAIDS but with continued

indolent pain Chronic Fatigue Syndrome

- Follow viral infection- Debilitating fatigue, fever, sore throat,

painful lymphadenopathy, myalgia, arthralgia, sleep disorder, headache

- No muscle weakness- Normal biopsy

Diagnosis Dx PM, DM, or IBM by examining muscle

enzymes, EMG, and muscle biopsy Most sensitive enzyme is CK.

- Increases 50x in active disease- Levels parallel disease activity- Can be normal in IBM or DM especially

with Connective tissue disease- Always elevated in PM

EMG findings- Short duration, low amp polyphasic units

on voluntary activation- Fibrillations, complex repetitive

discharges, positive sharp waves on increased spontaneous activity

- Mixed (polyphasic with short and long duration) indicate chronic process or fiber regeneration often seen in IBM

- Not diagnostic- Differentiate chronic vs active- Exclude neurogenic disorders

MRI not routine but used to guide during biopsy Muscle biopsy definitive test for Dx of

inflammatory myopathy1. PM: Primary inflammation with T cell

infiltrates, within muscle fascicles (endomysial) surrounding individual healthy fibers causing necrosis and phagocytosis. CD8/MHC-I lesion fundamental for dx. Chronic PM has inc connective tissue and positive reaction with alkaline phosphatase

2. DM: Endomysial inflammation is perivascular or interfascicular septae. Intramuscular blood vessels show endothelial hyperplasia w/ tuboreticular profiles, fibrin thrombi, obliteration of capillaries. Dx for DM, are microinfarcts w/ in muscle resulting to perfascicular atrophy (2 to 10 layers of atrophy at the periphery) even without inflammation.

3. IBM: Endomysial inflammation with T cell invading MHC-I nonvacuolated fibers. Or basophilic granules around slit like vacuole (rimmed) with filamentous inclusion seen on EM. Normal fibers replaced with connective tissue, hypertrophic fibers, and angulated or round fiber. May have eosinophilic grandules, or abnormal mitochondria with ragged red fibers.

Treatment Goal= improve muscle strength, improve

functioning via ADL, and ameliorate extramuscular manifestations.

CK levels decrease with improved strength. However do not just decrease levels without improving muscle strength.

Agents for PM and DM:1. Glucocorticoids

- Oral is initial tx- Use determined by efficacy and side

effects- High does 1mg/kg/day initially- After 3 to 4 weeks taper for 10

weeks to lowest possible- ADL better usually by 3rd month

- If no response after 3 months, discontinue

- DM respond better than PM- Steroid therapy is long term use

causing increased weakness and normal or unchanged CK levels

2. Other Immunosuppressive drugs- 75% require additional tx- Occurs w/ prednisone associated

complications such as resistance, adverse side effects, relapse, or rapidly progressive disease with respi failure

- Azathioprine is well tolerated with few side effects. 3mg/kd/day

- Methotrexate has faster onset. Associated with Jo- 1 anitbody MTX pneumonitis.

- Cyclophosphamide with significant toxicity

- Cyclosporine is inconsistent with mild benefit

- Mycophenolate Mofetil -

3. Immunomodulation- Good with refractory DM- IVIg improve strength and rash- Short lived benefit (<8 weeks)

Recommended Empirical Approach1. Step1- high does prednisone2. Step2- AZT or MTX3. IVIg4. Trial with guarded optimism based on

patient’s age, degree of disability, tolerance, experience with drug, and general health. Possible are cyclosporine, chlorambucil, cyclophosphamide (px w/ insterstitial lung disease), or mycophenolate.

Patient with PM who doesn’t respond to any immunotherapy most likely has IBM.

Associated with DM, Calcinosis, is difficult to treat. IBM generally resisitant to immunosuppressive tx.

- Prednisone with AZT or MTX for a few months in newly diagnosed pax

- Maintain on low dose, every other day prednisone or weekly MTX

- IVIg with minimal benefit. May be used to halt progression of choking episodes due to dysphagia

Prognosis 5 year survival rate for PM and DM is 95% 10 year survival rate is 84% Death from cardiac, pulmo, or other systemic

causes Worse prognosis in patients with delayed tx,

severe dysphagia or respi conditions, older px, and those with associated cancer

DM responds better and thus better prognosis than PM

30% with residual weakness even after tx Relapse may occur at any time IBM worst prognosis

- Most require cane, walker, wheelchair within 5 to 10 years of onset

- Older age of onset of IBM, more rapidly progressive course

KATRICHARDED